Edmond and Lily Safra Center of Brain Sciences, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Brain Struct Funct. 2013 Jan;218(1):59-72. doi: 10.1007/s00429-011-0376-z. Epub 2012 Jan 14.
Diverse stress stimuli induce long-lasting cognitive deficits, but the underlying molecular mechanisms are still incompletely understood. Here, we report three different stress models demonstrating that stress-inducible increases in microRNA-132 (miR-132) and consequent decreases in its acetylcholinesterase (AChE) target are causally involved. In a mild model of predator scent-induced anxiety, we demonstrate long-lasting hippocampal elevation of miR-132, accompanied by and associated with reduced AChE activity. Using lentiviral-mediated suppression of "synaptic" AChE-S mRNA, we quantified footshock stress-inducible changes in miR-132 and AChE and its corresponding cognitive damages. Stressed mice showed long-lasting impairments in the Morris water maze. In contrast, pre-stress injected AChE-suppressing lentivirus, but not a control virus, reduced hippocampal levels of both miR-132 and AChE and maintained similar cognitive performance to that of naïve, non-stressed mice. To dissociate between miR-132 and synaptic AChE-S as potential causes for stress-inducible cognitive deficits, we further used engineered TgR mice with enforced over-expression of the soluble "readthrough" AChE-R variant without the 3'-untranslated region binding site for miR-132. TgR mice displayed excess AChE-R in hippocampal neurons, enhanced c-fos labeling and correspondingly intensified reaction to the cholinergic agonist pilocarpine. They further showed excessive hippocampal expression of miR-132, accompanied by reduced host AChE-S mRNA and the GTPase activator p250GAP target of miR-132. At the behavioral level, TgR mice showed abnormal nocturnal locomotion patterns and serial maze mal-performance in spite of their reduced AChE-S levels. Our findings attribute stress-inducible cognitive impairments to cholinergic-mediated induction of miR-132 and consequently suppressed ACHE-S, opening venues for intercepting these miR-132-mediated damages.
多种应激刺激可诱导持久的认知障碍，但潜在的分子机制仍不完全清楚。在这里，我们报告了三种不同的应激模型，证明应激诱导的 microRNA-132（miR-132）增加及其乙酰胆碱酯酶（AChE）靶标的相应减少是因果相关的。在轻度捕食者气味诱导焦虑的模型中，我们证明了海马区 miR-132 的持久升高，伴随着和与 AChE 活性降低有关。使用慢病毒介导的抑制“突触”乙酰胆碱酯酶-S mRNA，我们定量了足底电击应激诱导的 miR-132 和 AChE 的变化及其相应的认知损伤。应激小鼠表现出长期的 Morris 水迷宫缺陷。相比之下，预先注射抑制乙酰胆碱酯酶的慢病毒，但不是对照病毒，降低了海马区 miR-132 和 AChE 的水平，并保持了与未受应激的正常小鼠相似的认知表现。为了区分 miR-132 和突触乙酰胆碱酯酶-S 作为应激诱导认知缺陷的潜在原因，我们进一步使用了具有强制过表达可溶性“通读”乙酰胆碱酯酶-R 变体的工程 TgR 小鼠，该变体没有与 miR-132 结合的 3'-非翻译区结合位点。TgR 小鼠在海马神经元中表现出过多的乙酰胆碱酯酶-R，增强了 c-fos 标记，相应地增强了对胆碱能激动剂毛果芸香碱的反应。它们进一步显示出 miR-132 在海马区的过度表达，伴随着宿主乙酰胆碱酯酶-S mRNA 和 miR-132 的 GTP 酶激活蛋白 p250GAP 靶标的减少。在行为水平上，尽管 TgR 小鼠的乙酰胆碱酯酶-S 水平降低，但它们表现出异常的夜间运动模式和连续的迷宫表现不佳。我们的研究结果将应激诱导的认知障碍归因于胆碱能介导的 miR-132 诱导，从而抑制了 ACHE-S，为阻断这些 miR-132 介导的损伤开辟了途径。
